Breast Neoplasms: Pritchard KI

Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, Anonymous00092. · Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #19470930 No free full text.

Abstract: PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.

Pritchard KI. · No affiliation provided · J Natl Cancer Inst. · Pubmed #18364499 links to  free full text

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Pritchard KI. · No affiliation provided · Br J Cancer. · Pubmed #17565339 links to  free full text

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Pritchard KI. · No affiliation provided · Br J Cancer. · Pubmed #17406347 links to  free full text

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Pritchard KI. · No affiliation provided · J Natl Cancer Inst. · Pubmed #17405988 links to  free full text

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Pritchard KI. · No affiliation provided · Ann Oncol. · Pubmed #16766581 links to  free full text

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Pritchard KI. · No affiliation provided · J Clin Oncol. · Pubmed #16009956 No free full text.

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Pater JL, Pritchard KI. · No affiliation provided · J Clin Oncol. · Pubmed #12637457 No free full text.

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Pritchard KI, Levine MN, Tu D. · No affiliation provided · J Clin Oncol. · Pubmed #12560425 No free full text.

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Pritchard KI. · No affiliation provided · J Clin Oncol. · Pubmed #12488402 No free full text.

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Pritchard KI. · No affiliation provided · J Clin Oncol. · Pubmed #11559715 No free full text.

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Bramwell VH, Pritchard KI. · No affiliation provided · Eur J Cancer. · Pubmed #10674005 No free full text.

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Pritchard KI. · Sunnybrook Odette Cancer Centre, Toronto, Canada. · Oncology (Williston Park). · Pubmed #19283918 No free full text.

Abstract: Endocrine therapy remains pivotal in the adjuvant therapy of premenopausal women with hormone receptor-positive breast cancer. Ovarian ablation, used alone, is effective in delaying recurrence and increasing survival in such women. When added to chemotherapy, it is less clear that this technique is effective, perhaps because of the endocrine ablative effect of chemotherapy. Adjuvant trials comparing ovarian ablation with or without tamoxifen to CMF-type chemotherapy (cyclophosphamide, methotrexate, fluorouracil) suggest that the endocrine therapy is equivalent to or better than this chemotherapy in women whose tumors express estrogen and/or progesterone receptors. Endocrine therapy with ovarian ablation, tamoxifen, or the combination is also useful in the metastatic setting in premenopausal women.

Saad F, Adachi JD, Brown JP, Canning LA, Gelmon KA, Josse RG, Pritchard KI. · Department of Surgery/Urology, Centre Hospitalier de l'Université de Montréal, University of Montreal, Montreal, Quebec, Canada. · J Clin Oncol. · Pubmed #18955443 No free full text.

Abstract: PURPOSE: Bone loss resulting from the treatment of breast and prostate cancer is an emerging problem. Bisphosphonates have a potential role in the prevention of this cancer treatment-induced bone loss (CTIBL). METHODS: Studies evaluating the incidence and prevalence of CTIBL in early breast and prostate cancer patients and trials evaluating the preventative role of bisphosphonates were identified by a search of the PubMed and Cochrane Library databases through the end of March 2008. Reference lists from retrieved articles were cross referenced, and further information was obtained from relevant scientific meetings. RESULTS: Several therapies commonly used in the treatment of women and men with breast and prostate cancers, in particular the aromatase inhibitors (AIs) for breast cancer and androgen deprivation therapy (ADT) for prostate cancer, are associated with significant bone loss and with an increase in fracture risk. The use of bisphosphonates seems to attenuate the bone loss, although the long-term impact remains unclear because of insufficient follow-up. CONCLUSION: Adjuvant endocrine therapy with an AI or androgen deprivation can be considered a risk factor for the development of osteopenia, osteoporosis, and bone fracture, which can be mitigated by appropriate bisphosphonate therapy. Clear identification of risk factors for osteoporosis in individual patients should aid treatment decisions about whether to use bisphosphonates when starting or switching to an AI or ADT. Patients need to be educated about this risk and other measures to avoid this complication, including lifestyle modifications that may benefit their general and bone health.

Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. · Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King Street West, Kingston, ON, Canada K7L 5P9. · Cancer Treat Rev. · Pubmed #18502589 No free full text.

Abstract: BACKGROUND: A systematic review was undertaken to evaluate the evidence for the use of trastuzumab as (neo)adjuvant therapy for women with HER-2/neu-positive breast cancer and to develop and support recommendations pertaining to its use across five domains: as a single-agent therapy, in combination with chemotherapy, methods to identify women who will benefit from it, adverse events associated with it, and optimal dose, schedule, and duration. METHODS: MEDLINE, EMBASE, the American Society of Clinical Oncology, the San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library were searched through May 2007 for reports of randomized controlled trials that met the inclusion criteria. RESULTS: Eight randomized trials, described across 23 citations, were identified. All six trials of adjuvant trastuzumab reported significantly improved disease-free survival (DFS) while 4 of 6 adjuvant trials showed significant improvement in overall survival (OS) for patients treated with trastuzumab over those that were not. Two trials of trastuzumab in the neoadjuvant setting reported significantly better pathological complete response (pCR) in patients treated with trastuzumab although both studies were limited by small sample size, and longer follow-up is needed. CONCLUSION: Although the optimal duration, schedule, and timing of adjuvant trastuzumab remains undefined, the bulk of the available evidence supports that adjuvant trastuzumab be offered for 1 year to all patients with HER-2-positive and node-positive or high-risk node-negative (tumour >or= 1cm in size) primary breast cancer who are receiving or have received (neo)adjuvant chemotherapy.

Stambolic V, Woodgett JR, Fantus IG, Pritchard KI, Goodwin PJ. · No affiliation provided · Breast Cancer Res Treat. · Pubmed #18438706 No free full text.

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Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O'Malley F, Dhesy-Thind B. · Sunnybrook Odette Cancer Centre, Department of Medicine, University of Toronto, 2075 Bayview Ave, Toronto, ON, Canada. · J Clin Oncol. · Pubmed #18258981 No free full text.

Abstract: HER2 overexpression or amplification has been shown to be associated with a poor prognostic effect in women with breast cancer. At least eight analyses based on randomized trials have examined the relationship between HER2 and the differential effect of anthracycline compared with non-anthracycline-containing regimens. Only three of these studies were sufficiently powered to show a significant interaction between HER2 and anthracycline- versus non-anthracycline-containing treatments, but because all of the study results tended to be in the same direction, it is not surprising that three recent meta-analyses of published data have suggested that anthracycline-containing regimens provide more benefit than non-anthracycline-containing regimens in women whose tumors are overexpressed or amplified (positive) for HER2. Since topoisomerase II is a known target of the anthracyclines, it has been postulated that this relationship is actually based on the proximity of HER2 to the topoisomerase II alpha gene (TOP2A) in the 17q chromosome. At least four recent studies have suggested that deletion and amplification of the TOP2A gene are associated with poor prognosis and are predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. However, in at least one of those studies, HER2 positivity was as or more predictive. Although it has been suggested that HER2 positivity is predictive of better response to higher-dose anthracycline-containing regimens compared with standard anthracycline-containing regimens and to taxane- compared with non-taxane-containing regimens, these relationships have not been robust or consistent. Additional studies will be required to clarify these relationships.

Anonymous00324, Clarke M, Coates AS, Darby SC, Davies C, Gelber RD, Godwin J, Goldhirsch A, Gray R, Peto R, Pritchard KI, Wood WC. · No affiliation provided · Lancet. · Pubmed #18177773 No free full text.

Abstract: BACKGROUND: The long-term effects of adjuvant polychemotherapy regimens in oestrogen-receptor-poor (ER-poor) breast cancer, and the extent to which these effects are modified by age or tamoxifen use, can be assessed by an updated meta-analysis of individual patient data from randomised trials. METHODS: Collaborative meta-analyses of individual patient data for about 6000 women with ER-poor breast cancer in 46 trials of polychemotherapy versus not (non-taxane-based polychemotherapy, typically about six cycles; trial start dates 1975-96, median 1984) and about 14 000 women with ER-poor breast cancer in 50 trials of tamoxifen versus not (some trials in the presence and some in the absence of polychemotherapy; trial start dates 1972-93, median 1982). FINDINGS: In women with ER-poor breast cancer, polychemotherapy significantly reduced recurrence, breast cancer mortality, and death from any cause, in those younger than 50 years and those aged 50-69 years at entry into trials of polychemotherapy versus not. In those aged younger than 50 years (1907 women, 15% node-positive), the 10-year risks were: recurrence 33% versus 45% (ratio of 10-year risks 0.73, 2p<0.00001), breast cancer mortality 24% versus 32% (ratio 0.73, 2p=0.0002), and death from any cause 25% versus 33% (ratio 0.75, 2p=0.0003). In women aged 50-69 years (3965 women, 58% node-positive), the 10-year risks were: recurrence 42% versus 52% (ratio 0.82, 2p<0.00001), breast cancer mortality 36% versus 42% (ratio 0.86, 2p=0.0004), and death from any cause 39% versus 45% (ratio 0.87, 2p=0.0009). Few were aged 70 years or older. Tamoxifen had little effect on recurrence or death in women who were classified in these trials as having ER-poor disease, and did not significantly modify the effects of polychemotherapy. INTERPRETATION: In women who had ER-poor breast cancer, and were either younger than 50 years or between 50 and 69 years, these older adjuvant polychemotherapy regimens were safe (ie, had little effect on mortality from causes other than breast cancer) and produced substantial and definite reductions in the 10-year risks of recurrence and death. Current and future chemotherapy regimens could well yield larger proportional reductions in breast cancer mortality.

Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. · Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5. · Cancer Treat Rev. · Pubmed #18164821 No free full text.

Abstract: BACKGROUND: A systematic review was undertaken to review the evidence for the use of third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) as adjuvant therapy for post-menopausal women with early-stage, hormone receptor-positive breast cancer and to develop and support recommendations for their use, with regard to three areas: aromatase inhibitors compared to tamoxifen, aromatase inhibitors in sequence with tamoxifen for a total of five years, and aromatase inhibitors given after five years of tamoxifen therapy. METHODS: MEDLINE, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched to May 2007 for reports of randomized controlled trials that met the inclusion criteria. RESULTS: Nine randomized controlled trials and one meta-analysis of three of these trials were identified that reported efficacy data. Eight of these trials reported significantly improved disease-free survival in the arms that involved aromatase inhibitors. The meta-analysis reported significantly improved overall survival among all patients, as did one individual trial. One trial of five years letrozole or placebo after five years tamoxifen found improved overall survival among node-positive patients. CONCLUSIONS: Aromatase inhibitors provide an alternative to tamoxifen as adjuvant therapy for post-menopausal, hormone-receptor-positive breast cancer patients. The options include anastrozole and letrozole for five years, as well as anastrozole and exemestane following two to three years of tamoxifen, for a total five years of hormonal therapy. Five years of letrozole should be considered following five years of tamoxifen. Patients receiving aromatase inhibitors should be monitored for changes in bone mineral density and for cardiovascular disease risk factors and outcomes.

Pritchard KI. · Toronto Sunnybrook Regional Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Canada M4N 3M5. · Breast. · Pubmed #17766115 No free full text.

Abstract: Women under 35 or 40 with primary breast cancer have a poor prognosis independent of other factors [Albain K, Allred C, Clark G. Breast cancer outcome and predictors of outcome: are there age differentials? J Natl Cancer Inst Monogr 1994;35-42]. In some recent studies, however, age is not independent in multivariate analyses, which include gene signatures [Van De Vijver M, He YD, Van'T Veer L, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.(132)]. Dissection of such molecular signatures may identify mechanisms, which can be targeted. Today, positive estrogen receptors identify women who require endocrine therapy, and HER2/neu positivity those who require herceptin and also benefit most from anthracyclines. Locoregional recurrences are also more common in younger women. Radiation boost therapy can reduce in-breast recurrence [Bartelink H, Horiot JC, Poortmans PM, Struikmans H, et al. Impact of radiation dose on local control, fibrosis and survival after breast conserving treatment: 10 year results of the EORTC trial 22881-10882. Br Cancer Res Treat 2006;100:S8-10]. There are also particular quality of life issues in young women, for whom fertility concerns and symptoms of premature menopause loom large. Some young women with lower risk may be candidates for endocrine therapy alone but it may be difficult to identify these with current prognostic and predictive factors. In the future more sophisticated molecular factors may identify those who require hormones alone, chemotherapy alone, newer biologic therapies, or combinations of these approaches.

Dhesy-Thind B, Pritchard KI, Messersmith H, O'Malley F, Elavathil L, Trudeau M. · Juravinski Cancer Centre, Hamilton, ON, Canada. · Breast Cancer Res Treat. · Pubmed #17636396 No free full text.

Abstract: BACKGROUND: Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. METHODS: A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. RESULTS: Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. CONCLUSIONS: Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.

Carlson RW, Hudis CA, Pritchard KI, Anonymous00094, Anonymous00095, Anonymous00096. · Department of Medicine, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA. · J Natl Compr Canc Netw. · Pubmed #17112447 No free full text.

Abstract: Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.

Pritchard KI, Abramson BL. · Toronto-Sunnybrook Regional Cancer Centre, Sunnybrook Health Sciences Centre, and the University of Toronto, Toronto, Ontario, Canada. · Drugs. · Pubmed #16978036 No free full text.

Abstract: Cardiovascular disease is the most frequent cause of death in North American women, and so death resulting from cardiovascular disease, rather than from malignancy, is not uncommon in breast cancer patients. This may be a consequence of the shared risk factors for developing breast cancer and cardiovascular disease, as well as the difficulty of managing cancer patients at higher risk for developing cardiovascular disease. Recently, much attention has focused on understanding the cardiovascular risk factors associated with breast cancer therapies. Tamoxifen has a lowering effect on serum lipids and is reported to decrease the risk of myocardial infarction but to increase the risk of thromboembolic events. Current data indicate that aromatase inhibitors (AIs) are not associated with an increased risk of thromboembolic or cerebrovascular events. Reports of a greater incidence of hypercholesterolaemia when AIs are compared head-to-head with tamoxifen may be a result of the intrinsic lipid-lowering effects of tamoxifen therapy and may be confounded by differences in data collection among trials. The incidence of cardiovascular events associated with AIs in large trials has been reported to be higher in trials comparing AIs with tamoxifen; comparisons within the MA.17 trial, which evaluated an AI versus placebo, did not show increases in hypercholesterolaemia or in cardiovascular events with the AI.When treating breast cancer patients, oncologists should consider the same positive lifestyle changes that are proposed to lower the risk of cardiovascular disease in patients who do not have breast cancer. Moreover, physicians should assess cardiovascular risk, and monitor and treat patients already diagnosed with or at risk for coronary heart disease, according to established guidelines.

Pritchard KI, Goss PE, Shepherd L. · Division of Clinical Trials and Epidemiology, Toronto-Sunnybrook Regional Cancer Center, 2075 Bayview Avenue, North York, Ont., Canada M4N 3M5. · Breast. · Pubmed #16500236 No free full text.

Abstract: Based upon the results of the NCIC CTG MA.17 trial, letrozole has become the only approved aromatase inhibitor (AI) in the extended adjuvant treatment setting following 5 years of tamoxifen therapy. In this trial, the AI letrozole decreased the overall risk of breast cancer recurrence by 42% compared with placebo in postmenopausal women completing 5 years of tamoxifen. The benefit of letrozole exceeded the expected difference after median follow-up of more than 2 years and led to the unblinding of the trial. The 30-month updated analyses found a 4.8%, 4-year disease-free survival improvement overall, an improvement in distant disease-free recurrence in both node-negative and node-positive patients, and a survival benefit for node-positive patients. Generally well tolerated, letrozole caused some adverse events including arthralgias and osteoporosis. However, results from the Zometa-Femara adjuvant synergy trial (Z-FAST) suggest that zoledronic acid, when used concomitantly with letrozole, is able to manage bone loss in postmenopausal women with early breast cancer.

Whelan TJ, Pritchard KI. · McMaster University, Hamilton, Ontario, Canada. · Clin Cancer Res. · Pubmed #16467124 links to  free full text

Abstract: PURPOSE: To review the health-related quality of life (QOL) of women treated with adjuvant hormonal therapy. EXPERIMENTAL DESIGN: To review the limited QOL data from randomized trials of tamoxifen versus placebo and ovarian ablation versus none. To discuss QOL results from randomized trials of aromatase inhibitors compared with tamoxifen or placebo for adjuvant therapy of postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. RESULTS: QOL is generally good in up to 3 years of follow-up with either tamoxifen or aromatase inhibitors. Vasomotor and sexual complaints remain problematic, however, in only a small proportion of women. There are fewer data regarding the QOL effects of ovarian ablation, which may nonetheless be more substantial. CONCLUSION: Tamoxifen and aromatase inhibitors cause specific vasomotor or gynecologic symptoms, which may affect sexual function. However, clinical benefits of these agents are generally achieved without major detrimental effect on overall QOL.